Pyridyl ethers and thioethers as ligands for nicotinic acetylcholine receptor and its therapeutic application

ABSTRACT

The present invention provides compounds of the formula:  
                 
 
     wherein m is 0, 1 or 2; p is 0 or 1; Y is O, S, S(O) or S(O) 2  and R 1  to R 7  are various substituents as selective modulators of the nicotinic acetylcholine receptor useful in the treatment of pain, Alzheimer&#39;s disease, memory loss or dementia or loss of motor function.

FIELD OF THE INVENTION

[0001] Briefly, according to the present invention, there are providedselective modulators of nicotinic acetylcholine receptors. Moreparticularly, the present invention provides pyridyl ethers andthioethers as selective nicotinic acetylcholine receptor agonists,partial agonists, antagonists or allosteric binding molecules useful inthe treatment of pain, Alzheimer's disease, memory loss or dementia orloss of motor function.

BACKGROUND OF THE INVENTION

[0002] Holladay, et. al., in “Identification and InitialStructure-Activity Relationship of(R)-5-(2-Azetidinylmethoxy)-2-chloropyridine (ABT594), a Potent, OrallyActive, Non-Opiate Analgesic Agent Acting via Neuronal NicotinicAcetylcholine Receptors”, 1998, J. Med. Chem., 41, 407, describe thepreparation of ABT594 and its therapeutic utility. A similar disclosureis made by Donnelly-Roberts, et. al., 1998, J. Pharmacol. Exp. Ther.,285, 777 & 787; Decker, et. al., 1998, Eur. J. Pharmacol., 346, 23 andin WO 98/25920; wherein ABT594 is contained within the generalstructure:

[0003] Abreo, et. al., in “Heterocyclic Ether Compounds that enhanceCognitive Function”, 1994, W.O. Patent 94/08992, describes thepreparation of heterocyclic ether compounds and its therapeutic utility.A similar disclosure is made in Abreo, et. al., 1996, J. Med. Chem. 39,817. Generally, the heterocyclic ether compounds have the structure:

[0004] where A is saturated heterocycle, B is unsaturated heterocycleand R is H or C₁₋₆alkyl.

[0005] Lin, et. al., in “3-Pyridyloxymethyl Heterocyclic ether Compoundsuseful in Controlling Chemical Synaptic Transmission”, 1997, U.S. Pat.No. 5,629,325, describe the preparation of pyridyl ether compound andits therapeutic utility. A similar disclosure is made by Lin, et. al.,1997, J. Med. Chem. 40, 385. Generally, the 3-Pyridyloxymethylheterocyclic ether compounds have the structure:

[0006] wherein R₁ is H or C₁₋₆alkyl; R₂ is H, F, Cl, vinyl or phenyl; Lis a C₁₋₆ linking group and R₃ is H or C₁₋₆alkyl.

[0007] Shanklin, et. al., in “Aryloxy and Aryloxyalklazetidines asAntiarrhythmic and Anticonvulsant Agents”, 1992, U.S. Pat. No.5,130,309, describe the preparation of Aryloxy andaryloxyalkyllazetidines and their therapeutic utilities. Generally, thedescribed azetidines have the formula:

[0008] wherein n is 0 to 3, R is H, C₁₋₄alkyl or arylalkyl and Ar isphenyl or substituted phenyl.

[0009] Cosford, et. al., in “Substituted Pyridine Derivatives, TheirPreparation and Their Use as Modulators of Acetylcholine Receptors”,1996, W.O. Patent 96/31475, describe the preparation of substitutedpyridine derivatives and its therapeutic utility. Generally, thepyridine derivative have the formula:

[0010] wherein A is 1-6 atoms bridging species linking pyridine and N, Bis 1-4 atoms bridging species linking N and Z, Z is H, C₁₋₆alkyl,alkynyl or aryl; R₃ is H or lower alkyl; and R₂, R₄, R₅, and R₆ are H,C₁₋₆alkyl, alkynyl, aryl or S-containing groups.

[0011] McDonald, et. al., in “Modulators of Acetylcholine Receptors”.1998, U.S. Pat. No. 5,723,477, describe the preparation of C-3substituted pyridyl compounds and its therapeutic utility. A similardisclosure is made in McDonald, et. al., 1997, U.S. Pat. No. 5,703,100;McDonald, et. al., 1997, U.S. Pat. No. 5,677,459; Menzaghi, et. al.,1997, J. Pharmacol Exp. Ther. 280, 373, 384, and 393; and Lloyd, et.al., 1998, Life Sci., 62, 1601. Generally, the C-3 substituted pyridylcompounds have the formula:

[0012] wherein A is 1-3 atom bridging moiety, forming a 5-7 memberedring; B is —O—, —S—, —NR¹⁰—, —CHR¹⁰—, ═CR¹⁰— or ═N—; R₂, R₄, R₅ and R₆are H, C₁₋₆alkyl, aryl, alkynyl, or O-, S-, or N(R)-containing group;and R₇ and R₉ are H, C₁₋₆alkyl, aryl, or alkynyl.

[0013] Caldwell, et. al., in “Method for Treatment of NeurodegenerativeDiseases” 1993, U.S. Pat. No. 5,212,188, describe the preparation ofalkenyl pyridyl compounds and its therapeutic utility. A similardisclosure is made in Bencherif, et. al., 1996 J. Pharmacol. Exp. Ther.,279, 1413 and 1422. Generally, the alkenyl pyridyl compounds have thegeneral formula:

[0014] wherein n is 1-5, R is H or C₁₋₅alkyl and X is halogen.

[0015] Crooks, et. al., in “Nicotinic Receptor Antagonists in theTreatment of Neuropharmacological Disorders” 1997, U.S. Pat. No.5,691,365, describe the preparation of nicotine analogs and itstherapeutic utility. Generally, the nicotinic analogues have thestructure:

[0016] wherein R is alkyl or branched alkyl with 2-19 carbon atoms,cycloalkyl, aralkyl or alkenyl.

[0017] Shen, et. al., in “7-Azabicyclo[2.2.2]-Heptane and -HepteneDerivatives as Cholinergic Receptor Ligands” 1996, W.O. Patent 96/06093,describe the preparation of 7-azabicyclo[2.2.2]-heptane and -heptenederivatives and their therapeutic utilities. A similar disclosure ismade by Shen, et. al., 1994, W.O. Patent 94/22868. Generally, theheptane and heptene derivatives have the formula:

[0018] wherein R₁, R₂, R₃, R₄, R₅, R₆, and R₇ are H, alkyl or analkyl-heteroatom containing group.

[0019] Dybes, et. al., in “Anticoccidal Cyclicaminoethanols and EstersThereof” 1978, U.S. Pat. No. 4,094,976, describe the preparation ofcyclicaminoethanols and esters and their therapeutic utilities.Generally, the cyclicaminoethanols have the formula:

[0020] wherein n is 3-5 and R is H or acyl radical.

[0021] Caldwell, et. al., in “Method for Treatment of NeurodegenerativeDisease” 1993, U.S. Pat. No. 5,214,060 describes the preparation of3-aminoalkylpyridines and its therapeutic utilities. Generally, the3-aminoalkylpyrimidines have the formula:

[0022] wherein R is C₁₋₇alkyl, X is substituent other than H, p is 1-5,m is 0-4 and n is 0-8.

[0023] There are two recent reviews on the topic of the nicotinicacetylcholine receptor: Holladay, et. al., in “Neuronal NicotinicAcetylcholine Receptors as Targets for Drug Discovery” 1997, J. Med.Chem., 40, 4169; and Holladay, et. al., in “Structure-ActivityRelationships of Nicotinic Acetylcholine Receptor Agonists as PotentialTreatments for Dementia” 1995, Drug Dev. Res., 35, 191.

SUMMARY OF THE INVENTION

[0024] There are provided by the present invention selective modulatorsof the nicotinic acetylcholine receptor of the general formula:

[0025] wherein

[0026] m is selected from 0, 1 or 2;

[0027] p is selected from 0 or 1;

[0028] Y is selected from the group consisting of O, S, S(O) and S(O)₂;

[0029] R¹ is independently selected from the group consisting of H—,HO—, O—, C₁₋₆alkyl-, C₂₋₆alkenyl-, C₂₋₆alkynyl-,C₃₋₆cycloalkylC₁₋₃alkyl-, phenylC₁₋₃alkyl-, —C(O)C₁₋₆alkyl, —C(O)phenyl,—C(O)C₁₋₆alkylphenyl, —C(O)OC₁,alkyl, —C(O)Ophenyl, —C(O)NHC₁₋₆alkyl,—C(O)N(C₁₋₆alkyl)₂ and —C(O)NHphenyl; wherein R¹ is optionallysubstituted on a carbon atom with one to three R^(a) substituents;wherein R^(a) is independently selected from the group consisting ofC₁₋₄alkyl, C₁₋₄alkoxy, hydroxyC₁ alkyl, carbomethoxy, acetoxy, nitro,Cl, Br and F;

[0030] R² is independently selected from the group consisting of H,C₁₋₆alkyl, phenyl and heteroaryl; wherein heteroaryl is as definedbelow;

[0031] R³ is selected from the group consisting of H, C₁₋₆alkyl, Cl, Brand F; with the proviso that if m is 0, then R³ is not Cl, Br or F; and

[0032] R⁴, R⁵, R⁶ and R⁷ are independently selected from the groupconsisting of hydrogen and selected radicals; wherein the radicals areselected from the group consisting of:

[0033] a) a trifluoromethyl group: —CF₃;

[0034] b) a halogen atom: —Br, —Cl, —F or —I;

[0035] c) a C₁₋₄alkoxy radical: —OC₁₋₄alkyl; wherein the alkyl isoptionally mono- or di-substituted by R^(q); wherein

[0036] R^(q) is selected from the group consisting of —OH, —OCH₃, —CN,—C(O)NH₂, —OC—(O)NH₂, CHO, —OC(O)N(CH₃)₂, —SO₂NH₂, SO₂N(CH₃)₂, —SOCH₃,SO₂CH₃, —F, —CF₃, —COOM^(a) (wherein M^(a) is selected from the groupconsisting of hydrogen, alkali metal, methyl and phenyl), tetrazolyl(wherein the point of attachment is the carbon atom of the tetrazolering and one of the nitrogen atoms is mono-substituted by M^(a), asdefined previously) and —SO₃ M^(b) (wherein M^(b) is selected from thegroup consisting of hydrogen and an alkali metal);

[0037] d) a hydroxy group: —OH;

[0038] e) a carbonyloxy radical: —O(C═O)R^(s); wherein

[0039] R^(s) is a group selected from the group consisting of C₁₋₄alkyl,phenyl and heteroaryl (each of which is optionally mono- ordi-substituted with R^(q), as defined previously);

[0040] wherein

[0041] heteroaryl is a monocyclic aromatic hydrocarbon group having fiveor six ring atoms, having at least one carbon atom which is the point ofattachment, having from one to three carbon atoms replaced by N in thecase of six ring atoms, having one carbon atom replaced by O, S or N inthe case of five ring atoms and, optionally, having up to threeadditional carbon atoms replaced by N;

[0042] f) a carbamoyloxy radical: —O(C═O)N(R^(Y))R^(z); wherein

[0043] R^(y) and R^(z) are independently selected from the groupconsisting of H, C₁₋₄alkyl (optionally mono- or di-substituted by R^(q),as defined previously), a three to five membered diradical to form aring wherein R^(y) and R^(z) are fused (optionally mono- ordi-substituted with R^(q), as defined previously) and a two to fivemembered diradical interrupted by —O—, —S—, —S(O)— or —S(O)₂— to form aring wherein R^(y) and R^(z) are fused (optionally mono- ordi-substituted with R^(q), as defined previously);

[0044] g) a sulfur radical: —(S═(O)_(n))—R^(s); wherein n is selectedfrom 0, 1 or 2 and R^(s) is as defined previously;

[0045] h) a sulfamoyl group: —SO₂N(R^(y))R^(z); wherein R^(y) and R^(z)are as defined previously;

[0046] i) an azido radical: N₃;

[0047] j) a formylamino group: —(N—R^(t))—(C═O)H; wherein

[0048] R^(t) is selected from the group consisting of H and C₁₋₄alkyl;wherein the alkyl chain is optionally mono- or di-substituted by R^(q),as defined previously;

[0049] k) a (C₁₋₄alkyl)carbonylamino radical:—(N—R^(t))—(C═O)—C₁₋₄alkyl; wherein

[0050] R^(t) is as defined previously; wherein the alkyl chain isoptionally mono-or di-substituted by R^(q), as defined previously;

[0051] l) a (C₁₋₄alkoxy)carbonylamino radical:—(N—R^(t))—(C═O)—O—C₁₋₄alkyl; wherein

[0052] R^(t) is as defined previously; wherein the alkyl chain isoptionally mono-substituted by R^(q), as defined previously;

[0053] m) a ureido group: —(N—R ^(t))—(C═O)N(R^(y))R^(z); wherein R_(t),R^(y) and R^(z) are as defined previously;

[0054] n) a sulfonamido group: —(N—R^(t))SO₂R^(s); wherein R^(s) andR^(t) are as defined previously;

[0055] o) a cyano group: —CN;

[0056] p) a (C₁₋₄alkyl)carbonyl radical; wherein the carbonyl isacetalized: —C(OMe)₂C₁₋₄ alkyl; wherein the alkyl is optionallymono-substituted by R^(q), as defined previously;

[0057] q) a carbonyl radical: —(C═O)R^(t); wherein R^(s) is as definedpreviously;

[0058] r) a hydroximinomethyl radical; wherein the oxygen or carbon atomis optionally substituted with a C₁₋₄alkyl group: —CR^(y)═NOR^(z);wherein R^(y) and R^(z) are as defined previously;

[0059] with the proviso that R_(y) and R_(z) may not be joined togetherto form a ring;

[0060] s) a (C₁₋₄alkoxy)carbonyl radical: —(C═O)OC₁₋₄alkyl; wherein thealkyl is optionally mono- or di-substituted by R_(q), as definedpreviously;

[0061] t) a carbamoyl radical: —(C═O)N(R_(y))R^(z); wherein R^(y) andR^(z) are as defined previously;

[0062] u) a N-hydroxycarbamoyl or N(C₁₋₄alkoxy)carbamoyl radical inwhich the nitrogen atom may additionally be substituted by a C₁₋₄alkylgroup: —(C═O)—N(OR_(y))R_(z); wherein R_(y) and R_(z) are as definedpreviously;

[0063] with the proviso that R_(y) and R_(z) may not be joined togetherto form a ring;

[0064] v) a thiocarbamoyl group: —(C═S)N(R_(y))R_(z); wherein R_(y) andR_(z) are as defined previously;

[0065] w) a carboxyl radical: —COOM^(b); wherein M^(b) is as definedpreviously;

[0066] x) a thiocyanate radical: —SCN;

[0067] y) a trifluoromethylthio radical: —SCF₃;

[0068] z) a tetrazolyl radical; wherein the point of attachment is thecarbon atom of the tetrazole ring and any one nitrogen atom ismono-substituted by a substituent selected from the group consisting ofhydrogen, an alkali metal and a C₁₋₄alkyl radical; wherein the C₁₋₄alkylradical is optionally mono- or di-substituted by R_(q), as definedpreviously;

[0069] aa) an anionic function selected from the group consisting ofphosphono [P═O(OM^(b))₂], alkylphosphono [P═O(OM^(b))-[O(C₁₋₄alkyl)]],alkylphosphinyl [P═O(OM^(b))-(C₁₋₄ alkyl)], phosphoramido[P═O(OM^(b))N(R^(y))R^(z) and P═O—(OM^(b))NHR^(x)], sulfino (SO₂ M^(b)),sulfo (SO₃ M^(b)) and acylsulfonamides selected from the groupconsisting of CONM^(b)SO₂R^(x), CONM^(b)SO₂N(R^(y))R^(z),SO₂NM^(b)CON(R^(y))R^(z) and SO₂NM^(b)CN; wherein

[0070] R^(x) is selected from the group consisting of phenyl andheteroaryl; wherein heteroaryl is as defined previously and the phenyland heteroaryl substituents are optionally mono- or di-substituted withR^(q), as defined previously; M^(b), R^(y) and R^(z) are as definedpreviously;

[0071] ab) a C₅-C₇ cycloalkyl group; wherein any one carbon atom in thering is replaced by a heteroatom selected from the group consisting ofO, S, NH and N(C₁₋₄alkyl); and, in which any one additional carbon atommay be replaced with NH or N(C₁₋₄alkyl) and in which at least one carbonatom adjacent to each nitrogen heteroatom has both of its attachedhydrogen atoms replaced by one oxygen whereby a carbonyl moiety isformed;

[0072] with the proviso that there are at most two carbonyl moietiespresent in the ring;

[0073] ac) a C₂-C₄ alkenyl radical; wherein the radical is optionallymono-substituted by a substituent selected from the group consisting ofany one of a) to ab) or is optionally mono-substituted by substituentsselected from the group consisting of phenyl, pyridyl, quinoline andisoquinoline; wherein each phenyl, pyridyl, quinoline or isoquinolinesubstituent is optionally mono- or di-substituted by R^(q), as definedpreviously;

[0074] ad) a C₁-C₄ alkyl radical;

[0075] ae) a C₁-C₄ alkyl mono-substituted by a substituent selected fromthe group consisting of any one of a) to ad);

[0076] af) a 2-oxazolidinonyl moiety; wherein the point of attachment isthe nitrogen atom of the oxazolidinone ring; wherein the ring oxygenatom is optionally replaced by a heteroatom selected from the groupconsisting of S and NR^(t) (wherein R^(t) is as defined previously) andone of the saturated carbon atoms of the oxazolidinone ring isoptionally mono-substituted by a substituent selected from the groupconsisting of any one of a) to ae);

[0077] ag) a C₂-C₄ alkynyl radical; wherein the radical is independentlyselected from the group consisting of any one of a) to af) andtrialkylsilyl;

[0078] ah) phenyl radicals

[0079] ai) bicyclic radicals; wherein the radical is independentlyselected from the group consisting of naphthyl, biphenyl, quinoline,indolizine, indole, isoindole, indoline, benzofuran, indazole,benzimidazole, purine, quinolizine, cinnoline, quinoxaline, phthalazineand quinazoline;

[0080] aj) heterocyclic radicals; wherein the radical is independentlyselected from the group consisting of furyl, thienyl, pyrazinyl,pyridazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl,thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, quinolinyl andisoquinolinyl; and

[0081] ak) aryl and heteroaryl radicals; wherein the radical isindependently selected from the group consisting of any one of ah)through aj); wherein the radical is substituted with one to twosubstituents independently selected from the group consisting of C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆alkoxyC₁-C₆alkyl,C₁-C₆alkoxyC₁-C₆alkoxy, C₁-C₆ thioalkyl, halogen, cyano, hydroxy, amino,nitro and C₁-C₆alkylamino, in which any terminal carbon atom may bereplaced by a group selected from the group consisting of carboxyl andC₂-C₆alkoxycarbonyl;

[0082] and pharmaceutically acceptable salts and esters thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0083] Relative to the above generic description, certain compounds ofthe general formula (I) are preferred. Particularly preferredembodiments are those compounds wherein:

[0084] R¹ is selected from the group consisting of hydrogen, methyl,ethyl, i-propyl, n-propyl, i-butyl, t-butyl, n-butyl, t-pentyl,n-pentyl, cyclohexylmethyl, 3-methyl-1-butyn-3-yl,4-dimethylaminobenzoyl, 2-hydroxymethylbenzoyl, acetyl,t-butyloxycarbonyl, ethoxycarbonyl, phenoxycarbonyl,4-nitrophenoxycarbonyl, 4-methoxyphenoxycarbonyl,4-carbomethoxyphenoxycarbonyl, 4-methyl phenoxycarbonyl,2,6-dimethylphenoxycarbonyl, 1-acetoxy-1-methyl-ethoxycarbonyl andbenzyloxycarbonyl;

[0085] R² is selected from the group consisting of hydrogen, methyl,ethyl, i-propyl, n-propyl, i-butyl, t-butyl, n-butyl, t-pentyl,n-pentyl, phenyl, thienyl and pyridyl;

[0086] R³ is selected from the group consisting of hydrogen, Cl, Br, F,methyl, ethyl, i-propyl, n-propyl, i-butyl, t-butyl, n-butyl, t-pentyland n-pentyl; preferably, R³ is hydrogen;

[0087] R⁴, R⁵, R⁶ and R⁷ are independently selected from the groupconsisting of hydrogen, —CH₃, —CH₂CH₃, —(CH₂)₃CH₃, —OCH₃, —SCH₃,-tetrazolyl, —COOH, —CH₂CONH₂, —CH₂CH₂SO₃H, —CONH₂, —SO₂NH₂, —SO₃H,—CON(CH₃)₂, —CN, —CH₂CN, —CH₂SCH₃, —CH₂SO₃H, —CH₂SOCH₃, —CH₂SO₂CH₃,—SO₂CH₃, —SOCH₃, —CH₂OCH₃, —N₃, —OCOCNH₂, —OH, —CHO, —CH₂P(O)(OCH₃)OH,—CF₃, CH₂OC(O)NH₂, —CH₂SO₂NH₂, —SCH₂CH₂CN, Br, Cl, F, —SCF₃, —CH₂SCF₃,—SCH₂CF₃, —COCH₃, —CH═NOH, —CONHOH, —C(S)NH₂, —OCOCH₃, —NHCOCH₃,—NHCO₂CH₃, —NHCONH₂, —NHSO₂CH₃, —SCN, —CH═CHCHO, —SCH₂CH₂OH, —CH₂OH,—CH═NOCH₂CO₂H, —CO₂CH₂CH₂OH and —SO₂NHCH₂CONH₂; and

[0088] heteroaryl is selected from the group consisting of pyrrole,pyridine (1 N); oxazole, thiazole, oxazine (1 N+10 or 1 S); thiadiazole(2N+1 S); furan (1O); thiophene (1S); pyrazole, imidazole, pyrimidine,pyrazine (2N); triazole, triazine (3N); and tetrazole (4N);

[0089] and pharmaceutically acceptable salts and esters thereof.

General Synthetic Methods

[0090] Representative compounds of the present invention can besynthesized in accordance with the general synthetic method schemesdescribed below and are illustrated more particularly in the specificsynthetic method schemes that follow. Since the schemes areillustrations, the invention should not be construed as being limited bythe chemical reactions and conditions expressed. The preparation of thevarious starting materials used in the schemes is well within the skillof persons versed in the art.

[0091] Compounds of the present invention may be made in a preferredone-step reaction scheme that may be preceded or followed by variousprocesses to obtain the desired substituents R¹ to R⁷ and is followed bydeprotection of N—R^(PR) to N—R¹. The preferred one-step reaction iscarried out by the conventional procedure known as the Mitsunobureaction [O. Mitsunobu, Synthesis, 1(1981)].

Scheme A

[0092] Referring to Scheme A, the pyridinyl alcohol Compound A1 isreacted under Mitsunobu conditions with the cyclic alkanol Compound A2to produce the desired base ring structure of the pyridinyl ethersherein. The reaction takes place in the presence of 1 or 2 equivalentseach of triphenylphosine and either diethyl- ordiisopropylazodicarboxylate in a suitable solvent such as benzene,toluene or THF at room temperature to reflux overnight. Subsequently,the protecting group R^(PR) is removed and replaced as desired. Suitableprotecting groups include C₁₋₈ substituted or unsubstituted alkyl; suchas, methyl, ethyl or propyl; or C₁₋₈ substituted acyl; such as, benzylcarboxylate, allyl carboxylate, acetyl, benzoyl or propanoyl. Manyspecific protecting groups R^(PR) are included within the definition ofR¹. Thus, the end product may conveniently have a substitution with R¹which was utilized in the synthesis as a nitrogen protecting group. Insuch case, deprotection is unnecessary.

[0093] A person skilled in the art can imagine other processes forproducing compounds of Formula (I). For example, leaving groups might beemployed on analogous starting material Compound A2′ wherein the hydroxyon Compound A2′ is replaced with with —OMs or —OTs and reacted withCompound A1 to form an ether linkage. The conditions for this reactionare well documented. The thioether linkage; wherein Y is S in Formula(I), can be produced in the manner employing Compound A2′ just describedusing analogous starting material Compound A1′, wherein hydroxy isreplaced with sulfhydryl. The thioether linkage can be oxidized to S(O)or S(O)₂ by the use of oxidizing agents such as the peroxides.

[0094] The terms used in describing the invention are commonly used andknown to those skilled in the art.

[0095] With reference to the above definitions, the term “alkyl” refersto a straight or branched chain aliphatic hydrocarbon radical.

[0096] The term “pharmaceutically acceptable salts and esters thereof”refers to those salt and ester forms of the compounds of the presentinvention which would be apparent to the pharmaceutical chemist, i.e.,those which are non-toxic and which would favorably affect thepharmacokinetic properties of said compounds of the present invention.Those compounds having favorable pharmacokinetic properties would beapparent to the pharmaceutical chemist, i.e., those which are non-toxicand which possess such pharmacokinetic properties to provide sufficientpalatability, absorption, distribution, metabolism and excretion. Otherfactors, more practical in nature, which are also important in theselection, are cost of raw materials, ease of crystallization, yield,stability, hygroscopicity, and flowability of the resulting bulk drug.

[0097] Examples of suitable salts include hydrobromic, hydroiodic,hydrochloric, perchloric, sulfuric, maleic, fumaric, malic, tartaric,citric, benzoic, mandelic, methanesulfonic, hydroethanesulfonic,benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic,p-toluenesulfonic, cyclohexanesulfamic and saccharic.

[0098] Examples of suitable esters include such esters wherein—COOM^(a), —COOM^(b) and —COOH are replaced withp-methoxybenzyloxycarbonyl, 2,4,6-trimethylbenzyloxycarbonyl,9-anthryloxycarbonyl, CH₃SCH₂COO—, tetrahydrofur-2-yloxycarbonyl,tetrahydropyran-2-yloxycarbonyl, fur-2-uloxycarbonyl, benzoylmethoxycarbonyl, p-nitrobenzyloxycarbonyl, 4-pyridylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl,t-butyloxycarbonyl, t-amyloxycarbonyl, diphenylmethoxycarbonyl,triphenylmethoxycarbonyl, adamantyloxycarbonyl,2-benzyloxyphenyloxycarbonyl, 4-methylthiophenyloxycarbonyl ortetrahydropyran-2-yloxycarbonyl.

[0099] The preferred compounds of the present invention are listed inTable 1 and include compounds of the formula: TABLE 1

wherein R¹ to R⁷ and m are selected concurrently from the groupconsisting of: Cpd m R¹ R² R⁴ R⁶ R⁷  1^(a) 0 H H H H H  2^(a) 1 CH₃ H HH H  3^(a) 0 CH₂CH₃ H H H H  4^(a) 0 CH(CH₃)₂ H H H H  5^(a) 0 H H H BrH  6^(a) 0 H H H H Cl  7^(a) 0 H H Cl H H  8^(a) 0 H H CH₃ H H  9^(a) 0CH₃ H H H Cl 10^(a) 0 CH₃ H H Br H 11^(a) 1 H H H H H 12^(a) 1 CH₃ H H HH 13^(a) 1 CH₂CH₃ H H H H 14^(a) 1 CH(CH₃)₂ H H H H 15^(a) 1 H H H Br H16^(a) 1 H H CH₃ H H 17^(a) 1 H H Cl H H 18^(a) 1 H H Br H H 19^(a) 1CH₃ H H Br H 20^(a) 1 CH₃ H H H Cl 21^(a) 1 CH₃ CH₃/CH₃ H H H 22^(b) 1 HH H H H 23^(b) 1 CH₃ H H H H 24^(b) 1 CH₂CH₃ H H H H 25^(b) 1 CH(CH₃)₂ HH H H 26^(b) 1 H H H Br H 27^(b) 1 H H CH₃ H H 28^(b) 1 H H Cl H H29^(b) 1 H H H H CH₃ 30^(b) 1 H H H H Cl 31^(b) 1 CH₃ H H Br H 32^(c) 1H H H H H 33^(c) 1 CH₃ H H H H 34^(c) 1 CH₂CH₃ H H H H 35^(c) 1 CH(CH₃)₂H H H H 36^(c) 1 H H H Br H 37^(c) 1 H H CH₃ H H 38^(c) 1 H H Cl H H39^(c) 1 H H H H CH₃ 40^(c) 1 H H H H Cl 41^(c) 1 CH₃ H H Br H 42^(b) 1H H H Br Cl 43^(b) 1 H H H Ph H 44^(b) 1 H H H (4-CN)Ph H 45^(b) 1 H H H(3-OMe)Ph H 46^(b) 1 H H H CCSi(CH₃)₃ H 47^(b) 1 H H H CC H 48^(b) 1 H HH (3-CN)Ph H 49^(b) 1 H H H (4-OMe) H 50^(b) 1 H H H (3-Cl)Ph H 51^(b) 1H H H (4-F)Ph H 52^(b) 1 H H H (3-Me)Ph H 53^(b) 1 H H H (4-SMe)Ph H54^(b) 1 H H H (3-F)Ph H 55^(b) 1 H H H (3-Cl-4-F)Ph H 56^(b) 1 H H H4-Pyr H 57^(b) 1 H H H Ph Cl 58^(b) 1 H H H (4-CN)Ph Cl 59^(b) 1 H H H(3-OMe)Ph Cl 60^(b) 1 H H H CCSi(CH₃)₃ Cl 61^(b) 1 H H H CC Cl 62^(b) 1H H H (3-CN)Ph Cl 63^(b) 1 H H H (4-OMe) Cl 64^(b) 1 H H H (3-Cl)Ph Cl65^(b) 1 H H H (4-F)Ph Cl 66^(b) 1 H H H (3-Me)Ph Cl 67^(b) 1 H H H(4-SMe)Ph Cl 68^(b) 1 H H H (3-F)Ph Cl 69^(b) 1 H H H (3-Cl-4-F)Ph Cl70^(b) 1 H H H 4-Pyr Cl 71^(a) 2 H H H H H 72^(a) 2 H H Cl H H 73^(a) 2CH₃ H H H H 74^(c) 2 H H H H H 75^(c) 2 H H Cl H H 76^(c) 2 CH₃ H H H H77^(c) 2 H H H Br H 78^(c) 2 CH₃ H H Br H 79^(c) 2 H H H H Cl

[0100] Compounds of Formula (I) may be used in pharmaceuticalcompositions to treat patients (humans and other primates) withdisorders related to the modulation of the nicotinic acetylcholinereceptor. Thus, the compounds are effective in the treatment of pain,Alzheimer's disease, memory loss/dementia or loss of motor function. Thecompounds are particularly effective in the treatment of pain.

[0101] The preferred route is oral administration, however compounds maybe administered by intravenous infusion or topical administration. Oraldoses range from about 0.05 mg to about 100 mg, daily. Some compounds ofthe invention may be orally dosed in the range from about 0.05 mg toabout 50 mg daily, while others may be dosed in the range from about0.05 mg to about 20 mg daily. Infusion doses can range from about 1.0 toabout 1.0×10⁴ mg/min of inhibitor, admixed with a pharmaceutical carrierover a period ranging from several minutes to several days. For topicaladministration, compounds of Formula (I) may be mixed with apharmaceutical carrier at a concentration from about 0.1% of drug toabout 10% of drug to vehicle.

[0102] The pharmaceutical compositions can be prepared usingconventional pharmaceutical excipients and compounding techniques. Oraldosage forms may be elixirs, syrups, capsules tablets and the like.Where the typical solid carrier is an inert substance such as lactose,starch, glucose, methyl cellulose, magnesium stearate, dicalciumphosphate, mannitol and the like; and typical liquid oral excipientsinclude ethanol, glycerol, water and the like. All excipients may bemixed as needed with disintegrants, diluents, granulating agents,lubricants, binders and the like using conventional techniques known tothose skilled in the art of preparing dosage forms. Parenteral dosageforms may be prepared using water or another sterile carrier.

Specific Synthetic Methods

[0103] In order to illustrate the invention the following examples areincluded. These examples do not limit the invention. They are only meantto suggest a method of practicing the invention. Those skilled in theart may find other methods of practicing the invention, which areobvious to them. However those methods are deemed to be within the scopeof this invention.

[0104] Reagents were purchased from Aldrich, Lancaster, Pfaltz & Bauer,TCI America, and used without further purification. ¹H NMR spectra werecollected on a Bruker AC-300 spectrometer. Chemical shifts are reportedwith respect to tetramethylsilane (TMS) δ_(H,C)=0.0 ppm. Spectra wereacquired at ambient temperature using DMSO-d₆, CD₃OD or CDCl₃. Massspectral analyses were performed on a Fisons instrument (Hewlett-PackardHPLC driven electrospray MS instrument). Analytical HPLC analyses wereperformed on a Hewlett-Packard liquid chromatography system (YMC column,4 mm×50 mm, 4 mm C₁₈, 1.0 mL/min, 8 min gradient from 95% aqueous media(0.1% TFA) to 95% CH₃CN (0.1% TFA), 220 and 260 nm).

EXAMPLE 1

[0105]

3-(3-Azetidinyloxy)-pyridine

[0106] Step (a): 1-t-Butoxycarbonyl-3-hydroxyazetidine

[0107] To 2.39 gm (10 mmol) of 1-(diphenylmethyl)-3-hydroxyazetidine in50 mL of ethanol was added 239 mg of Pd/C. The reaction mixture was thenhydrogenated at room temperature for 2 days. After 2 days, thesuspension was filtered through celite and washed with H₂O and MeOH. Thecombined filtrate was concentrated under reduced pressure. To the crudeproduct were then added 50 mL of a solution containing 25 mL of H₂O and25 mL of dioxane, 2.62 gm (12 mmol) of di-t-butyl dicarbonate, and 2.1mL (12 mmol) of DIEA at ice-bath temperature. The reaction mixture wasslowly warmed to room temperature and allowed to stir at roomtemperature for 5 h. After 5 h, solvents were removed in vacuo. To theresidue were added 100 mL of H₂O and 100 mL of ethyl acetate. Afterremoving the aqueous layer, the organic layer was washed with H₂O (2×50mL) and concentrated under reduced pressure. The crude product waspurified by flash chromatography (2:1, hexane:ethyl acetate) to obtain560 mg (32%) of a clear oil: ¹H NMR (300 MHz, CD₃OD) δ 4.48 (1H, m),4.10 (2H, t, J=4.5 Hz), 3.70 (2H, m), 1.43 (9H, s).

[0108] Step (b): 3-(1-t-Butoxycarbonyl-3-azetidinyloxy)-pyridine

[0109] To 315 mg (1.2 mmol) of PPh₃ in 5 mL of dry THF at −20° C. wasadded 189 μL (1.2 mmol) of DEAD dropwise. The solution was allowed tostir 10 min. at −20° C. After 10 min, a solution containing 173 mg (1mmol) of N-Boc-3-hydroxyazetidine and 2 mL of dry THF was addeddropwise. The solution was again allowed to stir 10 min at −20° C. After10 min, to the solution was added 95 mg (1 mmol) of 3-hydroxypyridine atonce. The solution was then slowly heated to 70° C. and allowed to stirat 70° C. overnight. Next day, solvent was removed under reducedpressure. The crude product was purified by flash chromatography (2:1,Hexane: Ethyl Acetate) to obtain 160 mg (64% yield) of a yellow oil: ¹HNMR (300 MHz, CD₃OD) δ 8.27 (1H, d, J=4.8 Hz), 8.18 (1H, d, J=2.7 Hz),7.23 (1H, m), 7.05 (1H, m), 4.92 (1H, m), 4.34-4.00 (2H, AB, J=6.6, 9.7Hz), 1.45 (9H, s).

[0110] Step (c): 3-(3-Azetidinyloxy)-pyridine

[0111] To 160 mg (0.64 mmol) of3-(1-t-butoxycarbonyl-3-azetidinyloxy)-pyridine was added 6 mL ofsolution containing 3 mL of TFA and 3 mL of CH₂Cl₂ at ice-bathtemperature. The reaction solution was slowly warmed to room temperatureand allowed to stir 50 min at room temperature. After 50 min, solventswere removed in vacuo and the crude product was purified by flashchromatography (9:1:0.05, CHCl₃:MeOH:conc. NH₄OH) to obtain 62 mg (67%)of a white solid: ¹H NMR (300 MHz, CD₃OD) δ 8.23 (2H, br s), 7.38 (2H,br d), 5.24 (2H, br s), 4.58 (2H, br d), 4.20 (2H, br d, J=9.8 Hz); Massspectrum (ESI) m/z 151.7 (M+H⁺).

EXAMPLE 2

[0112]

3-(3-Pyrrolidinyloxy)-pyridine

[0113] Step (a): 1-t-Butoxycarbonyl-3-hydroxypyrrolidine

[0114] To 831 μL (10 mmol) of 3-hydroxypyrrolidine were added 50 mL of asolution containing 25 mL of H₂O and 25 mL of dioxane, 2.62 gm (12 mmol)of di-t-butyl dicarbonate, and 2.1 mL (12 mmol) of DIEA at ice-bathtemperature. The reaction mixture was slowly warmed to room temperatureand allowed to stir at room temperature for 5 h. After 5 h, solventswere removed in vacuo. To the residue were added 100 mL of H₂O and 100mL of ethyl acetate. After removing the aqueous layer, the organic layerwas washed with H₂O (2×50 mL) and concentrated under reduced pressure.The crude product was purified by flash chromatography (2:1,hexane:ethyl acetate) to obtain 1.6 gm (85.6%) of a clear oil: ¹H NMR(300 MHz, CD₃OD) δ 4.35 (1H, m), 3.41-3.25 (4H, m), 1.95 (2H, m), 1.46(9H, s).

[0115] Step (b): 3-(1-t-Butoxycarbonyl-3-pyrrolidinyloxy)-pyridine

[0116] To 755 mg (2.88 mmol) of PPh₃ in 15 mL of dry THF at −20° C. wasadded 453 μL (2.88 mmol) of DEAD dropwise. The solution was allowed tostir 10 min. at −20° C. After 10 min, a solution containing 450 mg (2.4mmol) of 1-t-butoxycarbonyl-3-hydroxypyrrolidine and 5 mL of dry THF wasadded dropwise. The solution was again allowed to stir 10 min at −20° C.After 10 min, to the solution was added 229 mg (2.4 mmol) of3-hydroxypyridine at once. The solution was allowed to stir at roomtemperature overnight. Next day, solvent was removed under reducedpressure. The crude product was purified by flash chromatography (1:4,hexane:ethyl acetate) to obtain 1.3 gm of the product which containedsome triphenyl phospinoxide.

[0117] Step (c): 3-(3-Pyrrolidinyloxy)-pyridine

[0118] To 1.3 gm of 3-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-pyridinewas added 10 mL of solution containing 5 mL of TFA and 5 mL of CH₂Cl₂ atice-bath temperature. The reaction solution was slowly warmed to roomtemperature and allowed to stir 50 min at room temperature. After 50min, solvents were removed in vacuo and the crude product was purifiedby flash chromatography (9:1:0.05, CHCl₃:MeOH:conc. NH₄OH) to obtain 120mg (30.4% yield in two steps) of a clear oil: ¹H NMR (300 MHz, CD₃OD) δ8.21 (1H, d, J=2.6 Hz), 8.11 (1H, d, J=4.7 Hz), 7.38 (2H, m), 5.00 (1H,m), 3.13-2.88 (4H, m), 2,20-1.95 (2H, m); Mass spectrum (ESI) m/z 165.6(M+H⁺).

EXAMPLE 3

[0119]

3-(3-(S)-Pyrrolidinyloxy)-pyridine

[0120] By the procedure of Example 2, employing the appropriate3-(R)-hydroxypyrrolidine in place of 3-hydroxypyrrolidine,3-(3-(S)-pyrrolidinyloxy)-pyridine was produced as a clear oil: ¹H NMR(300 MHz, CD₃OD) δ 8.21 (1H, d, J=2.6 Hz), 8.11 (1H, d, J=3.6 Hz),7.43-7.34 (2H, m), 5.00 (1H, m), 3.12-2.87 (4H, m), 2,20-1.92 (2H, m);Mass spectrum (ESI) m/z 165.6 (M+H⁺).

EXAMPLE 4

[0121]

3-(3-(R)-Pyrrolidinyloxy)-pyridine

[0122] By the procedure of Example 2, employing the appropriate3-(S)-hydroxypyrrolidine in place of 3-hydroxypyrrolidine,3-(3-(R)-pyrrolidinyloxy)-pyridine was produced as a clear oil: ¹H NMR(300 MHz, CD₃OD) δ 8.21 (1H, d, J=2.6 Hz), 8.11 (1H, d, J=4.4 Hz),7.43-7.34 (2H, m), 5.00 (1H, m), 3.13-2.89 (4H, m), 2,20-1.95 (2H, m);Mass spectrum (ESI) m/z 165.6 (M+H⁺).

EXAMPLE 5

[0123]

3-(1-Methyl-3-(R)-pyrrolidinyloxy)-pyridine

[0124] To 164 mg (1 mmol) of 3-(3-(R)-pyrrolidinyloxy)-pyridine wereadded 300 mg (10 mmol) of paraformaldehyde, 314 mg (5 mmol) of NaCNBH₃,and 5 mL of dry THF at room temperature. To the suspension was added 2mL of trifluoroacetic acid dropwise. The suspension was allowed to stirat room temperature overnight. Next day, to the suspension was slowlyadded a mixture containing 20 mL of 4N NaOH and ice-chips. The mixturewas then extracted with ethyl acetate (2×40 mL). The combined organiclayers were dried over Na₂SO₄, and concentrated under reduced pressure.The crude product was purified by flash chromatography (15:1,CHCl₃:MeOH) to obtain 9 mg (5%) of a clear oil: ¹H NMR (300 MHz, CD₃OD)δ 8.19 (1H, d, J=1.7 Hz), 8.12 (1H, m). 7.38 (2H, m), 4.99 (1H, m),2.94-2.80 (3H, m), 2.52-1.93 (3H, m), 2.40 (3H, s); Mass spectrum (ESI)m/z 179.4 (M+H⁺).

EXAMPLE 6

[0125]

2-Chloro-5-(3-(R)-pyrrolidinyloxy)-pyridine

[0126] By the procedure of Example 2, employing the appropriate3-(S)-hydroxypyrrolidine in place of 3-hydroxypyrrolidine and2-chloro-5-hydroxypyridine in place of 3-hydroxypyridine,2-chloro-5-(3-(R)-pyrrolidinyloxy)-pyridine was produced as a clear oil:¹H NMR (300 MHz, CD₃OD) δ 8.10 (1H, s), 7.50 (1H, dd, J=2.3, 8.8 Hz),7.40 (1H, d, J=8.8 Hz), 5.28 (1H, s), 3.63-3.31 (4H, m), 2.34 (2H, m).

EXAMPLE 7

[0127]

3-(1-Methyl-3-pyrrolidinyloxy)-pyridine

[0128] To 629 mg (2.4 mmol) of PPh₃ in 13 mL of dry THF at −20° C. wasadded 378 μL (2.4 mmol) of DEAD dropwise. The solution was allowed tostir 10 min. at −20° C. After 10 min, a solution containing 220 μL (2.0mmol) of 1-methyl-3-hydroxypyrrolidine and 2 mL of dry THF was addeddropwise. The solution was again allowed to stir 10 min at −20° C. After10 min, to the solution was added 190 mg (2.0 mmol) of 3-hydroxypyridineat once. The solution was allowed to stir at room temperature overnight.Next day, solvent was removed under reduced pressure. The crude productwas purified by flash chromatography (9:1, CHCl₃:MeOH) to obtain 260 mg(72.9%) of a clear oil: ¹H NMR (300 MHz, CDCl₃) δ 8.26 (1H, d, J=2.6Hz), 8.20 (1H, d, J=4.2 Hz), 7.22-7.13 (2H, m), 4.85 (1H, m), 2.89-2.76(3H, m), 2.48-1.95 (3H, m), 2.40 (3H, s); Mass spectrum (ESI) m/z 179.6(M+H⁺).

EXAMPLE 8

[0129]

3-(1-Ethyl-3-pyrrolidinyloxy)-pyridine

[0130] By the procedure of Example 7, employing the appropriateN-ethyl-3-hydroxypyrrolidine in place of N-methyl-3-hydroxypyrrolidine,3-(1-ethyl-3-pyrrolidinyloxy)-pyridine was produced as a clear oil; ¹HNMR (300 MHz, CDCl₃) δ 8.27 (1H, d, J=2.6 Hz), 8.20 (1H, d, J=4.0 Hz),7.22-7.13 (2H, m), 4.87 (1H, m), 2.85 (3H, m), 2.58-1.95 (5H, m), 1.14(3H, t, J=7.2 Hz); Mass spectrum (ESI) m/z 193.5 (M+H⁺).

EXAMPLE 9

[0131]

3-(1-Isopropyl-3-pyrrolidinyloxy)-pyridine

[0132] By the procedure of Example 7, employing the appropriateN-isopropyl-3-hydroxypyrrolidine in place ofN-methyl-3-hydroxypyrrolidine,3-(1-isopropyl-3-pyrrolidinyloxy)-pyridine was produced as a lightyellow oil; ¹H NMR (300 MHz, CDCl₃) δ 8.26 (1H, d, J=2.6 Hz), 8.20 (1H,dd, J=4.3, 1.1 Hz), 7.23-7.13 (2H, m), 4,87 (1H, m), 3.08-1.97 (7H, m),1.16 (3H, d, J=3.4 Hz), 1.14 (3H, d, J=3.4 Hz); Mass spectrum (ESI) m/z207.5 (M+H⁺).

EXAMPLE 10

[0133]

3-(3-Piperidinyloxy)-pyridine

[0134] Step (a): 1-t-Butoxycarbonyl-3-hydroxypiperidine

[0135] To 1.38 gm (10 mmol) of 3-hydroxypyrrolidine were added 50 mL ofa solution containing 25 mL of H₂O and 25 mL of dioxane, 2.62 gm (12mmol) of di-t-butyl dicarbonate, and 2.1 mL (12 mmol) of DIEA atice-bath temperature. The reaction mixture was slowly warmed to roomtemperature and allowed to stir at room temperature for 5 h. After 5 h,solvents were removed in vacuo. To the residue were added 100 mL of H₂Oand 100 mL of ethyl acetate. After removing the aqueous layer, theorganic layer was washed with H₂O (2×50 mL) and concentrated underreduced pressure. The crude product was purified by flash chromatography(1:1, hexane:ethyl acetate) to obtain 1.97 gm (98.0%) of a white solid:¹H NMR (300 MHz, CD₃OD) δ 3.86-3.50 (3H, m), 2.98-2.81 (2H, m),1.92-1.73 (2H, m), 1.45 (9H, s), 1.50-1.36 (2H, m).

[0136] Step (b): 3-(1-t-Butoxycarbonyl-3-piperidinyloxy)-pyridine

[0137] To 629 mg (2.4 mmol) of PPh₃ in 13 mL of dry THF at −20° C. wasadded 378 μL (2.4 mmol) of DEAD dropwise. The solution was allowed tostir 10 min. at −20° C. After 10 min, a solution containing 402 mg (2.0mmol) of 1-t-butoxycarbonyl-3-hydroxypiperidine and 2 mL of dry THF wasadded dropwise. The solution was again allowed to stir 10 min at −20° C.After 10 min, to the solution was added 190 mg (2.0 mmol) of3-hydroxypyridine at once. The solution was allowed to stir at roomtemperature overnight. Next day, solvent was removed under reducedpressure. The crude product was purified by flash chromatography (1:1,hexane:ethyl acetate) to obtain 130 gm of the product which containedsome triphenyl phospinoxide.

[0138] Step (c): 3-(3-Piperidinyloxy)-pyridine

[0139] To 130 mg of 3-(1-t-butoxycarbonyl-3-piperidinyloxy)-pyridine wasadded 10 mL of solution containing 5 mL of TFA and 5 mL of CH₂Cl₂ atice-bath temperature. The reaction solution was slowly warmed to roomtemperature and allowed to stir 50 min at room temperature. After 50min, solvents were removed in vacuo and the crude product was purifiedby flash chromatography (9:1:0.05, CHCl₃:MeOH:conc. NH₄OH) to obtain 83mg (quantitative yield) of a clear oil: ¹H NMR (300 MHz, CD₃OD) δ 8.27(1H, d, J=2.7 Hz), 8.13 (1H, d, J=4.0 Hz), 7.49-7.34 (2H, m), 4.52 (1H,m), 3.20-2.80 (4H, m), 2.05-1.55 (4H, m); Mass spectrum (ESI) m/z 179.6(M+H⁺).

EXAMPLE 11

[0140]

3-(3-(S)-Piperidinyloxy)-pyridine

[0141] By the procedure of Example 10, employing the appropriate3-(R)-hydroxypiperidine in place of 3-hydroxypiperidine,3-(3-(S)-piperidinyloxy)-pyridine was produced as a clear oil: ¹H NMR(300 MHz, CD₃OD) δ 8.27 (1H, d, J=2.7 Hz), 8.13 (1H, d, J=4.0 Hz),7.49-7.34 (2H, m), 4.52 (1H, m), 3.20-2.80 (4H, m), 2.05-1.55 (4H, m);Mass spectrum (ESI) m/z 179.6 (M+H⁺).

EXAMPLE 12

[0142]

2-Chloro-3-bromo-5-(3-(R)-pyrrolidinyloxy)-pyridine

[0143] Step (a): 2-Chloro-3-bromo-5-(1-t-butoxycarbonyl3-(R)-pyrrolidinyloxy)-pyridine

[0144] To 3.15 gm (12 mmol) of PPh₃ in 100 mL of dry THF at −20° C. wasadded 1.89 mL (12 mmol) of DEAD dropwise. The solution was allowed tostir 10 min. at −20° C. After 10 min, a solution containing 1.87 gm (10mmol) of 1-t-butoxycarbonyl-3-(R)-hydroxypyrrolidine in 20 mL of dry THFwas added dropwise. The solution was again allowed to stir 10 min at−20° C. After 10 min, to the solution was added 2.08 gm (10 mmol) of2-chloro-3-bromo-5-hydroxypyridine at once. The solution was allowed tostir at room temperature overnight. Next day, solvent was removed underreduced pressure. The crude product was purified by flash chromatography(3:1, hexane:ethyl acetate) to obtain 3.65 gm (65%) of a foamy residue:¹H NMR (300 MHz, CD₃OD) δ 8.05 (1H, d, J=2.5 Hz), 7.78 (1H, d, J=2.5Hz), 5.09 (1H, s), 3.66-3.32 (4H, m), 2.18 (2H, m), 1.46 (9H, s).

[0145] Step (b): 2-Chloro-3-bromo-5-(3-(R)-pyrrolidinyloxy)-pyridine

[0146] By the procedure of Example 2c, employing the appropriate2-chloro-3-bromo-5-(1-t-butoxycarbonyl 3-(R)-pyrrolidinyloxy)-pyridine,2-chloro-3-bromo-5-(3-(R)-pyrrolidinyloxy)-pyridine was produced as aclear oil: ¹H NMR (300 MHz, CD₃OD) δ 8.05 (1H, d, J=2.5 Hz), 7.77 (1H,d, J=2.5 Hz), 5.09 (1H, s), 3.63-3.31 (4H, m), 2.34 (2H, m).

EXAMPLE 13

[0147]

2-Chloro-3-(4-cyano)phenyl-5-(3-(R)-pyrrolidinyloxy)-pyridine

[0148] Step (a): 2-Chloro-3-(4-cyano)phenyl-5-(1-t-butoxycarbonyl3-(R)-pyrrolidinyloxy)-pyridine

[0149] To 567 mg (1.5 mmol) of 2-chloro-3-bromo-5-(1-t-butoxycarbonyl3-(R)-pyrrolidinyloxy)-pyridine and 330 mg (2.25 mmol) of4-cyanophenylboronic acid were added 6 mL of toluene, 6 mL of absoluteethanol, 1.25 mL of [1 M] Na₂CO₃, 63 mg (1.5 mmol) of LiCl and 29 mg(0.025 mmol) of Pd(PPh₃)₄ under N₂ at room temperature. The suspensionwas slowly heated to 80° C. and allowed to stir overnight at 80° C. Nextday, supernatants were collected and concentrated in vacuo. The crudeproduct was purified by flash chromatography (5:2, hexane:ethyl acetate)to obtain 500 mg (83%) of a foamy residue.

[0150] Step (b):2-Chloro-3-(4-cyano)phenyl-5-(3-(R)-pyrrolidinyloxy)-pyridine

[0151] By the procedure of Example 2c, employing 490 mg (1.23 mmol) ofthe appropriate 2-chloro-3-(4-cyano)phenyl-5-(1-t-butoxycarbonyl3-(R)-pyrrolidinyloxy)-pyridine, 340 mg (75%) of2-chloro-3-(4-cyano)phenyl-5-(3-(R)-pyrrolidinyloxy)-pyridine wasproduced as a clear oil: ¹H NMR (300 MHz, CD₃OD) δ 8.11 (1H, d, J=2.9Hz), 7.84 (2H, d, J=8.2 Hz), 7.66 (2H, d, J=8.3 Hz), 7.46 (1H, d, J=2.9Hz), 5.07 (1H, s), 3.34-2.91 (4H, m), 2.19-2.04 (2H, m).

EXAMPLE 14

[0152]

2-Chloro-3-(3-methoxy)phenyl-5-(3-(R)-pyrrolidinyloxy)-pyridine

[0153] By the procedure of Example 13, employing 570 mg (1.41 mmol) ofthe appropriate 2-chloro-3-(3-methoxy)phenyl-5-(1-t-butoxycarbonyl3-(R)-pyrrolidinyloxy)-pyridine, 380 mg (72%) of2-chloro-3-(3-methoxy)phenyl-5-(3-(R)-pyrrolidinyloxy)-pyridine wasproduced as a clear oil: ¹H NMR (300 MHz, CD₃OD) δ 8.05 (1H, d, J=2.9Hz), 7.38 (2H, m), 7.01 (3H, m), 5.06 (1H, s), 3.83 (3H, s), 3.16-2.90(4H, m), 2.21-2.03 (2H, m).

EXAMPLE 15

[0154]

2-Chloro-3-(4-trimethylsilylethynyl)phenyl-5-(3-(R)-pyrrolidinyloxy)-pyridine

[0155] Step (a):2-Chloro-3-(4-trimethylsilylethynyl)phenyl-5-(1-t-butoxycarbonyl-3-(R)-pyrrolidinyloxy)-pyridine

[0156] To 1.68 gm (4.4 mmol) of 2-chloro-3-bromo-5-(1-t-butoxycarbonyl3-(R)-pyrrolidinyloxy)-pyridine in 45 mL of dry THF were added 4.5 mL ofEt₃N, 1.26 mL (8.9 mmol) of trimethylsilylacetylene, 257 mg (0.2 mmol)of Pd(PPh₃)₄, and 42 mg (0.2 mmol) of CuI at room temperature. Thesuspension was slowly heated to 70° C. and allowed to stir 4 h at 70° C.After 4 h, the suspension was cooled to room temperature and allowed tostir 3 days at room temperature. After 3 days, the crude product wasconcentrated and purified by flash chromatography (6:1, hexane:ethylacetate) to obtain 1.3 gm (74%) of a yellow oil: ¹H NMR (300 MHz, CD₃OD)δ 8.03 (1H, s), 7.55 (1H, d, J=2.8 Hz), 5.07 (1H, s), 3.65-3.35 (4H, m),2.16-2.00 (2H, m), 1.46 (9H, s), 0.26 (9H, s).

[0157] Step (b):2-Chloro-3-(4-trimethylsilylethynyl)phenyl-5-(3-(R)-pyrrolidinyloxy)-pyridine

[0158] By the procedure of Example 2c, employing 650 mg (1.66 mmol) ofthe appropriate2-chloro-3-(4-trimethylsilylethynyl)phenyl-5-(1-t-butoxycarbonyl-3-(R)-pyrrolidinyloxy)-pyridine,380 mg (63%) of2-chloro-3-(4-trimethylsilylethynyl)phenyl-5-(3-(R)-pyrrolidinyloxy)-pyridinewas produced as a clear oil: ¹H NMR (300 MHz, CD₃OD) δ 8.03 (1H, d,J=2.9 Hz), 7.55 (1H, d, J=2.9 Hz), 5.09 (1H, s), 3.34-3.11 (4H, m),2.19-2.10 (2H, m), 0.26 (9H, s).

Biological Protocols EXAMPLE 1 α₄β₂ Nicotinic Acetylcholine Receptor(α₄β₂ nAChR)

[0159] In Vitro Protocol for Determination of α₄β₂ nAChR BindingPotencies of Ligands

[0160] Binding of ³H-cytisine to neuronal nicotinic acetylcholinereceptors was accomplished using crude synaptic membrane preparationsfrom rat cerebral cortex, striatum and hippocampus. Either fresh orfrozen membranes were homogenized in ˜50 volumes of 10 mM HEPES(N-2-Hydroxyethylpiperazine-N′-2-Ethanesulfonic acid, pH 7.4) andcentrifuged at 42,000×g. The P₂ fraction was resuspended in ˜40 volumesof 10 mM HEPES and centrifuged at 42,000×g. This step was repeated andthe P₂ fraction was resuspended in 25 volumes (e.g. 1 g of original into25 mL) of a medium comprising Na⁺-HEPES buffer (10 mM, pH 7.4), 5 mMMgCl₂, 0.01% powdered bovine serum albumin (BSA) and 100 mM NaCl. Toinitiate the binding reaction, test compound (100 μL), Na-HEPES bufferedincubation medium (400 μL), ³H-cytisine (250 μL) and the suspension ofbiological membranes (250 μL) were mixed, and then the samples wereincubated at 23° C. for 40 minutes. The binding reaction was terminatedby filtration using a Brandel Cell Harvester and the amount of bound³H-cytisine for each sample was quantitated using a Wallac LKB 1205Betaplate liquid scintillation counter. All test compounds were screenedat 10 μM in quadruplicate. Nonspecific binding was determined using 10μM (+)-epibatidine to block all binding of ³H-cytisine to the α₄β₂nAChR. The activity of each test compound was calculated as follows.After correcting for nonspecific binding, the percent inhibition ofspecific binding (total binding minus nonspecific) was calculated. Eachactive compound was further tested at five concentrations to generate aconcentration-inhibition curve. The IC₅₀ values were determined usingthe Prism (GraphPad Software) nonlinear regression program.

EXAMPLE 2 α₇ nicotinic Acetylcholine Receptor (α₇nAChR)

[0161] In Vitro Protocol for Determination of α₇ nAChR BindingPotencies' of Ligands

[0162] Binding of ³H-MLA (methylcaconitine) to neuronal nicotinicacetylcholine receptors was accomplished using crude synaptic membranepreparations from rat cerebral cortex, striatum and hippocampus. Eitherfresh or frozen membranes were homogenized in ˜50 volumes of 10 mM HEPES(N-2-Hydroxyethylpiperazine-N′-2-Ethanesulfonic acid, pH 7.4) andcentrifuged at 42,000×g. The P₂ fraction was resuspended in ˜40 volumesof 10 mM HEPES and centrifuged at 42,000×g. This step was repeated andthe P₂ fraction was resuspended in 25 volumes (e.g. 1 g of original into25 mL) of a medium comprised of Na⁺-HEPES buffer (10 mM, pH 7.4), 5 mMMgCl₂, 0.01% powdered bovine serum albumin (BSA), and 100 mM NaCl. Toinitiate the binding reaction, test compound (100 μL), Na-HEPES bufferedincubation medium (400 μL), ³H-MLA (250 μL) and the suspension ofbiological membranes (250 μL) were mixed, and then the samples wereincubated at 23° C. for 40 minutes. The binding reaction was terminatedby filtration using a Brandel Cell Harvester, and the amount of bound³H-MLA for each sample was quantitated using a Wallac LKB 1205 Betaplateliquid scintillation counter. All test compounds were screened at 10 μMin quadruplicate. Nonspecific binding was determined using 10 μM MLA toblock all binding of ³H-MLA to the α₇ nAChR. The activity of each testcompound was calculated as follows. After correcting for nonspecificbinding, the percent inhibition of specific binding (total binding minusnonspecific) was calculated. Each active compound was further tested atfive concentrations to generate a concentration-inhibition curve. TheIC₅₀ values were determined using the Prism (GraphPad Software)nonlinear regression program.

Biological Data

[0163] Table 2 provides the test results from the Biological Protocolsfor the compounds from Examples 1 to 15 provided by the SpecificSynthetic Methods TABLE 2 Ex # α4β₂ (nM) α₇ (% Inh @ 10 uM) 1  46^(a) 212 209 −15 3 449 5 4  45 11 5 544 20 6 466 20 7  92 22 8  71^(a) 18 9 30^(a) 19 10 204 19 11 673 86 12  94 11 13  22 26 14  58 33 15  25 22

What is claimed is:
 1. A compound of the general formula:

wherein m is selected from 0, 1 or 2; p is selected from 0 or 1; Y isselected from the group consisting of O, S, S(O) and S(O)₂; R¹ isindependently selected from the group consisting of H—, HO—, O—,C₁₋₆alkyl-, C₂,alkenyl-, C₂₋₆alkynyl-, C₃₋₆cycloalkylC₁₋₃alkyl-,phenylC₁₋₃alkyl-, —C(O)C₁₋₁alkyl, —C(O)phenyl, —C(O)C₁₋₆alkylphenyl,—C(O)OC₁₋₆alkyl, —C(O)Ophenyl, —C(O)NHC₁₋₆alkyl, —C(O)N(C₁₋₆alkyl)₂ and—C(O)NHphenyl; wherein R¹ is optionally substituted on a carbon atomwith one to three R^(a) substituents; wherein R^(a) is independentlyselected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy,hydroxyC₁₋₄alkyl, carbomethoxy, acetoxy, nitro, Cl, Br and F; R² isindependently selected from the group consisting of H, C₁₋₆alkyl, phenyland heteroaryl; wherein heteroaryl is as defined below; R³ is selectedfrom the group consisting of H, C₁₋₆alkyl, Cl, Br and F; with theproviso that if m is 0, then R³ is not Cl, Br or F; and R⁴, R⁵, R⁶ andR⁷ are independently selected from the group consisting of hydrogen andselected radicals; wherein the radicals are selected from the groupconsisting of: a) a trifluoromethyl group: —CF₃; b) a halogen atom: —Br,—Cl, —F or —I; c) a C₁₋₄alkoxy radical: —OC₁₋₄ alkyl; wherein the alkylis optionally mono- or di-substituted by R^(q); wherein R^(q) isselected from the group consisting of —OH, —OCH₃, —CN, —C(O)NH₂,—OC—(O)NH₂, CHO, —OC(O)N(CH₃)₂, —SO₂NH₂, SO₂N(CH₃)₂, —SOCH₃, SO₂CH₃, —F,—CF₃, —COOM^(a) (wherein M^(a) is selected from the group consisting ofhydrogen, alkali metal, methyl and phenyl), tetrazolyl (wherein thepoint of attachment is the carbon atom of the tetrazole ring and one ofthe nitrogen atoms is mono-substituted by M^(a), as defined previously)and —SO₃ M^(b) (wherein M^(b) is selected from the group consisting ofhydrogen and an alkali metal); d) a hydroxy group: —OH; e) a carbonyloxyradical: —O(C═O)R^(s); wherein R^(s) is a group selected from the groupconsisting of C₁₋₄alkyl, phenyl and heteroaryl (each of which isoptionally mono- or di-substituted with R^(q), as defined previously);wherein heteroaryl is a monocyclic aromatic hydrocarbon group havingfive or six ring atoms, having at least one carbon atom which is thepoint of attachment, having from one to three carbon atoms replaced by Nin the case of six ring atoms, having one carbon atom replaced by O, Sor N in the case of five ring atoms and, optionally, having up to threeadditional carbon atoms replaced by N; f) a carbamoyloxy radical:—O(C═O)N(R^(y))R^(z); wherein R^(y) and R^(z) are independently selectedfrom the group consisting of H, C₁₋₄alkyl (optionally mono- ordi-substituted by R^(q), as defined previously), a three to fivemembered diradical to form a ring wherein R^(y) and R^(z) are fused(optionally mono- or di-substituted with R^(q), as defined previously)and a two to five membered diradical interrupted by —O—, —S—, —S(O)— or—S(O)₂— to form a ring wherein R^(y) and R^(z) are fused (optionallymono- or di-substituted with R^(q), as defined previously); g) a sulfurradical: —(S═(O)_(n))—R^(s); wherein n is selected from 0, 1 or 2 andR^(s) is as defined previously; h) a sulfamoyl group: —SO₂N(R^(y))R^(z);wherein R^(y) and R^(z) are as defined previously; i) an azido radical:N₃; j) a formylamino group: —(N—R^(t))—(C═O)H; wherein R^(t) is selectedfrom the group consisting of H and C₁₋₄alkyl; wherein the alkyl chain isoptionally mono- or di-substituted by R^(q), as defined previously; k) a(C₁₋₄alkyl)carbonylamino radical: —(N—R^(t))—(C═O)—C, alkyl; whereinR^(t) is as defined previously, wherein the alkyl chain is optionallymono-or di-substituted by R^(q), as defined previously; l) a(C₁₋₄alkoxy)carbonylamino radical: —(N—R^(t))—(C═O)—O—C₁₋₄alkyl; whereinR^(t) is as defined previously; wherein the alkyl chain is optionallymono-substituted by R^(q), as defined previously; m) a ureido group:—(N—R^(t))—(C═O)N(R^(y))R^(z); wherein R^(t), R^(y) and R^(z) are asdefined previously; n) a sulfonamido group: —(N—R^(t))SO₂R^(s); whereinR^(s) and R^(t) are as defined previously; o) a cyano group: —CN; p) a(C₁₋₄alkyl)carbonyl radical; wherein the carbonyl is acetalized:—C(OMe)₂C₁₋₄ alkyl; wherein the alkyl is optionally mono-substituted byR^(q), as defined previously; q) a carbonyl radical: —(C═O)R^(s);wherein R^(s) is as defined previously; r) a hydroximinomethyl radical;wherein the oxygen or carbon atom is optionally substituted with aC₁₋₄alkyl group: —CR^(y)═NOR^(z); wherein R^(y) and R^(z) are as definedpreviously; with the proviso that R^(y) and R^(z) may not be joinedtogether to form a ring; s) a (C₁₋₄alkoxy)carbonyl radical:—(C═O)OC₁₋₁alkyl; wherein the alkyl is optionally mono- ordi-substituted by R^(t), as defined previously; t) a carbarnoyl radical:—(C═O)N(R^(y))R^(z); wherein R^(y) and R^(z) are as defined previously;u) a N-hydroxycarbamoyl or N(C₁₋₄alkoxy)carbamoyl radical in which thenitrogen atom may additionally be substituted by a C₁₋₄alkyl group:—(C═O)—N(OR^(y))R^(z); wherein R^(y) and R^(z) are as definedpreviously; with the proviso that R^(y) and R^(z) may not be joinedtogether to form a ring; v) a thiocarbamoyl group: —(C═S)N(R^(y))R^(z);wherein R^(y) and R^(z) are as defined previously; w) a carboxylradical: —COOM^(b); wherein M^(b) is as defined previously; x) athiocyanate radical: —SCN; y) a trifluoromethylthio radical: —SCF₃; z) atetrazolyl radical; wherein the point of attachment is the carbon atomof the tetrazole ring and any one nitrogen atom is mono-substituted by asubstituent selected from the group consisting of hydrogen, an alkalimetal and a C₁₋₄alkyl radical; wherein the C₁₋₄alkyl radical isoptionally mono- or di-substituted by R^(t), as defined previously; aa)an anionic function selected from the group consisting of phosphono[P═O(OM^(b))₂], alkylphosphono [P═O(OM^(b))-[O(C₁₋₄alkyl)]]alkylphosphinyl [P═O(OM^(b))-(C₁₋₄ alkyl)], phosphoramido[P═O(OM^(b))N(R^(y))R^(z) and P═O—(OM^(b))NHR^(x)], sulfino (SO₂ M^(b)),sulfo (SO₃ M^(b)) and acylsulfonamides selected from the groupconsisting of CONM^(b)SO₂R^(x), CONM^(b)SO₂N(R^(y))R^(z),SO₂NM^(b)CON(R^(y))R^(z) and SO₂NM^(b)CN; wherein R^(x) is selected fromthe group consisting of phenyl and heteroaryl; wherein heteroaryl is asdefined previously and the phenyl and heteroaryl substituents areoptionally mono- or di-substituted with R^(q), as defined previously;M^(b), R^(y) and R^(z) are as defined previously; ab) a C₅-C₇ cycloalkylgroup; wherein any one carbon atom in the ring is replaced by aheteroatom selected from the group consisting of O, S, NH andN(C₁₋₄alkyl); and, in which one additional carbon atom may be replacedwith NH or N(C₁₋₄alkyl) and in which at least one carbon atom adjacentto each nitrogen heteroatom has both of its attached hydrogen atomsreplaced by one oxygen whereby a carbonyl moiety is formed; with theproviso that there are at most two carbonyl moieties present in thering; ac) a C₂-C₄ alkenyl radical; wherein the radical is optionallymono-substituted by a substituent selected from the group consisting ofany one of a) to ab) or is optionally mono-substituted by substituentsselected from the group consisting of phenyl, pyridyl, quinoline andisoquinoline; wherein each phenyl, pyridyl, quinoline or isoquinolinesubstituent is optionally mono- or di-substituted by R^(q), as definedpreviously; ad) a C₁-C₄ alkyl radical; ae) a C₁-C₄ alkylmono-substituted by a substituent selected from the group consisting ofany one of a) to ad); af) a 2-oxazolidinonyl moiety; wherein the pointof attachment is the nitrogen atom of the oxazolidinone ring; whereinthe ring oxygen atom is optionally replaced by a heteroatom selectedfrom the group consisting of S and NR^(t) (wherein R^(t) is as definedpreviously) and one of the saturated carbon atoms of the oxazolidinonering is optionally mono-substituted by a substituent selected from thegroup consisting of any one of a) to ae); ag) a C₂-C₄ alkynyl radical;wherein the radical is independently selected from the group consistingof any one of a) to af) and trialkylsilyl, ah) phenyl radicals ai)bicyclic radicals; wherein the radical is independently selected fromthe group consisting of naphthyl, biphenyl, quinoline, indolizine,indole, isoindole, indoline, benzofuran, indazole, benzimidazole,purine, quinolizine, cinnoline, quinoxaline, phthalazine andquinazoline; aj) heterocyclic radicals; wherein the radical isindependently selected from the group consisting of furyl, thienyl,pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl,indolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, quinolinyl andisoquinolinyl; and ak) aryl and heteroaryl radicals; wherein the radicalis independently selected from the group consisting of any one of ah)through aj); wherein the radical is substituted with one or twosubstituents independently selected from the group consisting of C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆alkoxyC₁-C₆alkyl,C₁-C₆alkoxyC₁-C₆alkoxy, C₁-C₆ thioalkyl, halogen, cyano, hydroxy, amino,nitro and C₁-C₆alkylamino, in which any terminal carbon atom may bereplaced by a group selected from the group consisting of carboxyl andC₂-C₆alkoxycarbonyl; and pharmaceutically acceptable salts and estersthereof.
 2. The compound of claim 1 wherein the compound is a selectivemodulator of the nicotinic acetylcholine receptor.
 3. The compound ofclaim 1 wherein the compound is an antagonist of the nicotinicacetylcholine receptor.
 4. The compound of claim 1 wherein the compoundis an agonist of the nicotinic acetylcholine receptor.
 5. The compoundof claim 1 wherein R¹ is selected from the group consisting of hydrogen,methyl, ethyl, i-propyl, n-propyl, i-butyl, t-butyl, n-butyl, t-pentyl,n-pentyl, cyclohexylmethyl, 3-methyl-1-butyn-3-yl,4-dimethylaminobenzoyl, 2-hydroxymethylbenzoyl, acetyl,t-butyloxycarbonyl, ethoxycarbonyl, phenoxycarbonyl,4-nitrophenoxycarbonyl, 4-methoxyphenoxycarbonyl,4-carbomethoxyphenoxycarbonyl, 4-methylphenoxycarbonyl,2,6-dimethylphenoxycarbonyl, 1-acetoxy-1-methyl-ethoxycarbonyl andbenzyloxycarbonyl.
 6. The compound of claim 1 wherein R² is selectedfrom the group consisting of hydrogen, methyl, ethyl, i-propyl,n-propyl, i-butyl, t-butyl, n-butyl, t-pentyl, n-pentyl, phenyl, thienyland pyridyl.
 7. The compound of claim 1 wherein R³ is selected from thegroup consisting of hydrogen, Cl, Br, F, methyl, ethyl, i-propyl,n-propyl, i-butyl, t-butyl, n-butyl, t-pentyl and n-pentyl.
 8. Thecompound of claim 1 wherein R³ is hydrogen.
 9. The compound of claim 1wherein R⁴, R⁵, R⁶ and R⁷ are independently selected from the groupconsisting of hydrogen, —CH₃, —CH₂CH₃, —(CH₂)₃CH₃, —OCH₃, —SCH₃,-tetrazolyl, —COOH, —CH₂CONH₂, —CH₂CH₂SO₃H, —CONH₂, —SO₂NH₂, —SO₃H,—CON(CH₃)₂, —CN, —CH₂CN, —CH₂SCH₃, —CH₂SO₃H, —CH₂SOCH₃, —CH₂SO₂CH₃,—SO₂CH₃, —SOCH₃, —CH₂OCH₃, —N₃, —OCOCNH₂, —OH, —CHO, —CH₂P(O)(OCH₃)OH,—CF₃, CH₂OC(O)NH₂, —CH₂SO₂NH₂, —SCH₂CH₂CN, Br, Cl, F, —SCF₃, —CH₂SCF₃,—SCH₂CF₃, —COCH₃, —CH═NOH, —CONHOH, —C(S)NH₂, —OCOCH₃, —NHCOCH₃,—NHCO₂CH₃, —NHCONH₂, —NHSO₂CH₃, —SCN, —CH═CHCHO, —SCH₂CH₂OH, —CH₂OH,—CH═NOCH₂CO₂H, —CO₂CH₂CH₂OH and —SO₂NHCH₂CONH₂.
 10. The compound ofclaim 1 wherein heteroaryl is selected from the group consisting ofpyrrole, pyridine, oxazole, thiazole, oxazine, thiadiazole, furan,thiophene, pyrazole, imidazole, pyrimidine, pyrazine, triazole, triazineand tetrazole.
 11. The compound of claim 1 wherein said pharmaceuticallyacceptable salt is selected from the group consisting of hydrobromic,hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric, malic,tartaric, citric, benzoic, mandelic, methanesulfonic,hydroethanesulfonic, benzenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic andsaccharic.
 12. The compound of claim 1 wherein the pharmaceuticallyacceptable ester is an ester wherein —COOM^(a), —COOM^(b) and —COOH areselected from the group consisting of p-methoxybenzyloxycarbonyl,2,4,6-trimethylbenzyloxycarbonyl, 9-anthryloxycarbonyl, CH₃SCH₂COO—,tetrahydrofur-2-yloxycarbonyl, tetrahydropyran-2-yloxycarbonyl,fur-2-uloxycarbonyl, benzoylmethoxycarbonyl, p-nitrobenzyloxycarbonyl,4-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,2,2,2-tribromoethoxycarbonyl, t-butyloxycarbonyl, t-amyloxycarbonyl,diphenylmethoxycarbonyl, triphenylmethoxycarbonyl, adamantyloxycarbonyl,2-benzyloxyphenyloxycarbonyl, 4-methylthiophenyloxycarbonyl ortetrahydropyran-2-yloxycarbonyl.
 13. The compound of claim 1 wherein thecompound has the general formula:

wherein R¹ to R⁷ and m are selected concurrently from the groupconsisting of: Cpd m R¹ R² R⁴ R⁶ R⁷  1^(a) 0 H H H H H  2^(a) 1 CH₃ H HH H  3^(a) 0 CH₂CH₃ H H H H  4^(a) 0 CH(CH₃)₂ H H H H  5^(a) 0 H H H BrH  6^(a) 0 H H H H Cl  7^(a) 0 H H Cl H H  8^(a) 0 H H CH₃ H H  9^(a) 0CH₃ H H H Cl 10^(a) 0 CH₃ H H Br H 11^(a) 1 H H H H H 12^(a) 1 CH₃ H H HH 13^(a) 1 CH₂CH₃ H H H H 14^(a) 1 CH(CH₃)₂ H H H H 15^(a) 1 H H H Br H16^(a) 1 H H CH₃ H H 17^(a) 1 H H Cl H H 18^(a) 1 H H Br H H 19^(a) 1CH₃ H H Br H 20^(a) 1 CH₃ H H H Cl 21^(a) 1 CH₃ CH₃/CH₃ H H H 22^(b) 1 HH H H H 23^(b) 1 CH₃ H H H H 24^(b) 1 CH₂CH₃ H H H H 25^(b) 1 CH(CH₃)₂ HH H H 26^(b) 1 H H H Br H 27^(b) 1 H H CH₃ H H 28^(b) 1 H H Cl H H29^(b) 1 H H H H CH₃ 30^(b) 1 H H H H Cl 31^(b) 1 CH₃ H H Br H 32^(c) 1H H H H H 33^(c) 1 CH₃ H H H H 34^(c) 1 CH₂CH₃ H H H H 35^(c) 1 CH(CH₃)₂H H H H 36^(c) 1 H H H Br H 37^(c) 1 H H CH₃ H H 38^(c) 1 H H Cl H H39^(c) 1 H H H H CH₃ 40^(c) 1 H H H H Cl 41^(c) 1 CH₃ H H Br H 42^(b) 1H H H Br Cl 43^(b) 1 H H H Ph H 44^(b) 1 H H H (4-CN)Ph H 45^(b) 1 H H H(3-OMe)Ph H 46^(b) 1 H H H CCSi(CH₃)₃ H 47^(b) 1 H H H CC H 48^(b) 1 H HH (3-CN)Ph H 49^(b) 1 H H H (4-OMe) H 50^(b) 1 H H H (3-Cl)Ph H 51^(b) 1H H H (4-F)Ph H 52^(b) 1 H H H (3-Me)Ph H 53^(b) 1 H H H (4-SMe)Ph H54^(b) 1 H H H (3-F)Ph H 55^(b) 1 H H H (3-Cl-4-F)Ph H 56^(b) 1 H H H4-Pyr H 57^(b) 1 H H H Ph Cl 58^(b) 1 H H H (4-CN)Ph Cl 59^(b) 1 H H H(3-OMe)Ph Cl 60^(b) I H H H CCSi(CH₃)₃ Cl 61^(b) I H H H CC Cl 62^(b) IH H H (3-CN)Ph Cl 63^(b) 1 H H H (4-OMe) Cl 64^(b) I H H H (3-Cl)Ph Cl65^(b) 1 H H H (4-F)Ph Cl 66^(b) 1 H H H (3-Me)Ph Cl 67^(b) 1 H H H(4-SMe)Ph Cl 68^(b) 1 H H H (3-F)Ph Cl 69^(b) 1 H H H (3-Cl-4-F)Ph Cl70^(b) 1 H H H 4-Pyr Cl 71^(a) 2 H H H H H 72^(a) 2 H H Cl H H 73^(a) 2CH₃ H H H H 74^(c) 2 H H H H H 75^(c) 2 H H Cl H H 76^(c) 2 CH₃ H H H H77^(c) 2 H H H Br H 78^(c) 2 CH₃ H H Br H 79^(c) 2 H H H H Cl


14. The compound of claim 1 wherein the compound is selected from thegroup consisting of:


15. A method for treating a condition or disease the pathogenesis ofwhich may be regulated by modulation of the nicotinic acetylcholinereceptor which comprises the step of administering to a patientsuffering from such a condition or disease an effective amount of acompound of the general formula:

wherein m is selected from 0, 1 or 2; p is selected from 0 or 1; Y isselected from the group consisting of O, S, S(O) and S(O)₂; R¹ isindependently selected from the group consisting of H—, HO—, O—,C₁₋₆alkyl-, C₂₋₆alkenyl-, C₂₋₆alkynyl-, C₃₋₆cycloalkylC₁₋₃alkyl-,phenylC₁₋₃alkyl-, —C(O)C₁₋₆alkyl, —C(O)phenyl, —C(O)C₁₋₆alkylphenyl,—C(O)OC₁₋₆alkyl, —C(O)Ophenyl, —C(O)NHC₁₋₆alkyl, —C(O)N(C₁₋₆alkyl)₂ and—C(O)NHphenyl; wherein R¹ is optionally substituted on a carbon atomwith one to three R^(a) substituents; wherein R^(a) is independentlyselected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy,hydroxyC₁₋₄alkyl, carbomethoxy, acetoxy, nitro, Cl, Br and F; R² isindependently selected from the group consisting of H, C₁₋₆alkyl, phenyland heteroaryl; wherein heteroaryl is as defined below; R³ is selectedfrom the group consisting of H, C₁₋₆alkyl, Cl, Br and F; with theproviso that if m is 0, then R³ is not Cl, Br or F; and R⁴, R⁵, R⁶ and.R⁷ are independently selected from the group consisting of hydrogen andselected radicals; wherein the radicals are selected from the groupconsisting of: a) a trifluoromethyl group: —CF₃; b) a halogen atom: —Br,—Cl, —F or —I; c) a C₁₋₄alkoxy radical: —OC₁₋₄ alkyl; wherein the alkylis optionally mono- or di-substituted by R^(q); wherein R^(q) isselected from the group consisting of-OH, —OCH₃, —CN, —C(O)NH₂,—OC—(O)NH₂, CHO, —OC(O)N(CH₃)₂, —SO₂NH₂, SO₂N(CH₃)₂, —SOCH₃, SO₂CH₃, —F,—CF₃, —COOM^(a) (wherein M^(a) is selected from the group consisting ofhydrogen, alkali metal, methyl and phenyl), tetrazolyl (wherein thepoint of attachment is the carbon atom of the tetrazole ring and one ofthe nitrogen atoms is mono-substituted by M^(a), as defined previously)and SO₃ M^(b) (wherein M^(b) is selected from the group consisting ofhydrogen and an alkali metal); d) a hydroxy group: —OH; e) a carbonyloxyradical: —O(C═O)R^(s); wherein R^(s) is a group selected from the groupconsisting of C₁₋₄alkyl, phenyl and heteroaryl (each of which isoptionally mono- or di-substituted with R^(q), as defined previously);wherein heteroaryl is a monocyclic aromatic hydrocarbon group havingfive or six ring atoms, having at least one carbon atom which is thepoint of attachment; having from one to three carbon atoms replaced by Nin the case of six ring atoms, having one carbon atom replaced by O, Sor N in the case of five ring atoms and, optionally, having up to threeadditional carbon atoms replaced by N; f) a carbamoyloxy radical:—O(C═O)N(R^(y))R^(z); wherein R^(y) and R^(z) are independently selectedfrom the group consisting of H, C₁₋₄alkyl (optionally mono- ordi-substituted by R^(q), as defined previously), a three to fivemembered diradical to form a ring wherein R^(y) and R^(z) are fused(optionally mono- or di-substituted with R^(q), as defined previously)and a two to five membered diradical interrupted by —O—, —S—, —S(O)— or—S(O)₂— to form a ring wherein R^(y) and R^(z) are fused (optionallymono- or di-substituted with R^(q), as defined previously); g) a sulfurradical: —(S═(O)_(n))—R^(s); wherein n is selected from 0, 1 or 2 andR^(s) is as defined previously; h) a sulfamoyl group: —SO₂N(R^(y))R^(z);wherein R^(y) and R^(z) are as defined previously; i) an azido radical:N₃; j) a formylamino group: —(N—R^(t))—(C═O)H; wherein R^(t) is selectedfrom the group consisting of H and C₁₋₄alkyl; wherein the alkyl chain isoptionally mono- or di-substituted by R^(q), as defined previously; k) a(C₁₋₄alkyl)carbonylamino radical: —(N—R^(t))—(C═O)—C₁₋₆alkyl; whereinR^(t) is as defined previously; wherein the alkyl chain is optionallymono-or di-substituted by R^(q), as defined previously; l) a(C₁₋₄alkoxy)carbonylamino radical: —(N—R^(t))—(C═O)—O—C₁₋₄alkyl; whereinR^(t) is as defined previously; wherein the alkyl chain is optionallymono-substituted by R^(q), as defined previously; m) a ureido group:—(N—R^(t))—(C═O)N(R^(y))R^(z); wherein R^(t), R^(y) and R^(z) are asdefined previously; n) a sulfonamido group: —(N—R^(t))SO₂R^(s); whereinR^(s) and R^(t) are as defined previously; o) a cyano group: —CN; p) a(C₁₋₄alkyl)carbonyl radical; wherein the carbonyl is acetalized:—C(OMe)₂C₁₋₄ alkyl; wherein the alkyl is optionally mono-substituted byR^(q), as defined previously; q) a carbonyl radical: —(C═O)R^(s);wherein R^(s) is as defined previously; r) a hydroximinomethyl radical;wherein the oxygen or carbon atom is optionally substituted with aC₁₋₄alkyl group: —CR^(y)═NOR^(z); wherein R^(y) and R^(z) are as definedpreviously; with the proviso that R^(y) and R^(z) may not be joinedtogether to form a ring; s) a (C₁₋₄alkoxy)carbonyl radical:—(C═O)OC₁₋₄alkyl; wherein the alkyl is optionally mono- ordi-substituted by R^(q), as defined previously; t) a carbamoyl radical:—(C═O)N(R^(y))R^(z); wherein R^(y) and R^(z) are as defined previously;u) a N-hydroxycarbamoyl or N(C₁₋₄alkoxy)carbamoyl radical in which thenitrogen atom may additionally be substituted by a C₁₋₄alkyl group:—(C═O)—N(OR^(y))R^(z); wherein R^(y) and R^(z) are as definedpreviously; with the proviso that R^(y) and R^(z) may not be joinedtogether to form a ring; v) a thiocarbamoyl group: —(C═S)N(R^(y))R^(z);wherein R^(y) and R^(z) are as defined previously; w) a carboxylradical: —COOM^(b); wherein Mb is as defined previously; x) athiocyanate radical: —SCN; y) a trifluoromethylthio radical: —SCF₃; z) atetrazolyl radical; wherein the point of attachment is the carbon atomof the tetrazole ring and any one nitrogen atom is mono-substituted by asubstituent selected from the group consisting of hydrogen, an alkalimetal and a C₁₋₄alkyl radical; wherein the C₁₋₄alkyl radical isoptionally mono- or di-substituted by R^(q), as defined previously; aa)an anionic function selected from the group consisting of phosphono[P═O(OM^(b))²], alkylphosphono [P═O(OM^(b))-[O(C₁₋₄alkyl)]],alkylphosphinyl [P═O(OM^(b))-(C₁₋₆alkyl)], phosphoramido[P═O(OM^(b))N(R^(y))R^(z) and P═O—(OM^(b))NHR^(x)], sulfino (SO₂ M^(b)),sulfo (SO₃ M^(b)) and acylsulfonamides selected from the groupconsisting of CONM^(b)SO₂R^(x), CONM^(b)SO₂N(R^(y))R^(z), SO₂NM^(b)CON(R^(y))R^(z) and SO₂NM^(b)CN; wherein R^(x) is selected from thegroup consisting of phenyl and heteroaryl; wherein heteroaryl is asdefined previously and the phenyl and heteroaryl substituents areoptionally mono- or di-substituted with R^(q), as defined previously;Mb, R^(y) and R^(z) are as defined previously; ab) a C₅-C₇ cycloalkylgroup; wherein any one carbon atom in the ring is replaced by aheteroatom selected from the group consisting of O, S, NH andN(C₁₋₄alkyl); and, in which one additional carbon atom may be replacedwith NH or N(C₁₋₆alkyl) and in which at least one carbon atom adjacentto each nitrogen heteroatom has both of its attached hydrogen atomsreplaced by one oxygen whereby a carbonyl moiety is formed; with theproviso that there are at most two carbonyl moieties present in thering; ac) a C₂-C₄ alkenyl radical; wherein the radical is optionallymono-substituted by a substituent selected from the group consisting ofany one of a) to ab) or is optionally mono-substituted by substituentsselected from the group consisting of phenyl, pyridyl, quinoline andisoquinoline; wherein each phenyl, pyridyl, quinoline or isoquinolinesubstituent is optionally mono- or di-substituted by R^(q), as definedpreviously; ad) a C₁-C₄ alkyl radical; ae) a C₁-C₄ alkylmono-substituted by a substituent selected from the group consisting ofany one of a) to ad); af) a 2-oxazolidinonyl moiety; wherein the pointof attachment is the nitrogen atom of the oxazolidinone ring; whereinthe ring oxygen atom is optionally replaced by a heteroatom selectedfrom the group consisting of S and NR^(t) (wherein R^(t) is as definedpreviously) and one of the saturated carbon atoms of the oxazolidinonering is optionally mono-substituted by a substituent selected from thegroup consisting of any one of a) to ae); ag) a C₂-C₄ alkynyl radical;wherein the radical is independently selected from the group consistingof any one of a) to af) and trialkylsilyl; ah) phenyl radicals ai)bicyclic radicals; wherein the radical is independently selected fromthe group consisting of naphthyl, biphenyl, quinoline, indolizine,indole, isoindole, indoline, benzofuran, indazole, benzimidazole,purine, quinolizine, cinnoline, quinoxaline, phthalazine andquinazoline; aj) heterocyclic radicals; wherein the radical isindependently selected from the group consisting of furyl, thienyl,pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl,indolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, quinolinyl andisoquinolinyl; and ak) aryl and heteroaryl radicals; wherein the radicalis independently selected from the group consisting of any one of ah)through aj); wherein the radical is substituted with one or twosubstituents independently selected from the group consisting of C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆alkoxyC₁-C₆alkyl,C₁-C₆alkoxyC₁-C₆alkoxy, C₁-C₆ thioalkyl, halogen, cyano, hydroxy, amino,nitro and C₁-C₆alkylamino, in which any terminal carbon atom may bereplaced by a group selected from the group consisting of carboxyl andC₂-C₆alkoxycarbonyl; and pharmaceutically acceptable salts and estersthereof.
 16. The method of claim 15 wherein the compound is a selectivemodulator of the nicotinic acetylcholine receptor.
 17. The method ofclaim 15 wherein the compound is an antagonist of the nicotinicacetylcholine receptor.
 18. The method of claim 15 wherein the compoundis an agonist of the nicotinic acetylcholine receptor.
 19. The method ofclaim 15 wherein the condition is acute or chronic pain and the patientis in need of analgesia.
 20. The method of claim 15 wherein thecondition or disease is Alzheimer's disease, memory loss or dementia orloss of motor function.
 21. A pharmaceutical composition for treating acondition or a disease the pathogenesis of which may be regulated bymodulation of the nicotinic acetylcholine receptor which comprises abiologically acceptable carrier or diluent and an effective amount of acompound of the following formula effective to treat a patient sufferingfrom the condition or disease:

wherein m is selected from 0, 1 or 2; p is selected from 0 or 1; Y isselected from the group consisting of O, S, S(O) and S(O)₂; R¹ isindependently selected from the group consisting of H—, HO—, O—,C₁₋₆alkyl-, C₂,alkenyl-, C₂₋₆alkynyl-, C₃₋₄cycloalkylC₁₋₃alkyl-,phenylC₁₋₃alkyl-, —C(O)C₁₋₆alkyl, —C(O)phenyl, —C(O)C₁₋₆alkylphenyl,—C(O)OC₁₋₆alkyl, —C(O)Ophenyl, —C(O)NHC₁₋₆alkyl, —C(O)N(C₁₋₄alkyl)₂ and—C(O)NHphenyl; wherein R¹ is optionally substituted on a carbon atomwith one to three R_(a) substituents; wherein R_(a) is independentlyselected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy,hydroxyC₁₋₄alkyl, carbomethoxy, acetoxy, nitro, Cl, Br and F; R² isindependently selected from the group consisting of H, C₁₋₆alkyl, phenyland heteroaryl; wherein heteroaryl is as defined below; R³ is selectedfrom the group consisting of H, C₁₋₆alkyl, Cl, Br and F; with theproviso that if m is 0, then R³ is not Cl, Br or F; and R⁴, R⁵, R⁶ andR⁷ are independently selected from the group consisting of hydrogen andselected radicals; wherein the radicals are selected from the groupconsisting of: a) a trifluoromethyl group: —CF₃; b) a halogen atom: —Br,—Cl, —F or —I; c) a C₁₋₄alkoxy radical: —OC₁₋₄alkyl; wherein the alkylis optionally mono- or di-substituted by R^(q); wherein R^(q) isselected from the group consisting of —OH, —OCH₃, —CN, —C(O)NH₂,—OC—(O)NH₂, CHO, —OC(O)N(CH₃)₂, —SO₂NH₂, SO₂N(CH₃)₂₁—SOCH₃, SO₂CH₃, —F,—CF₃, —COOM^(a) (wherein M^(a) is selected from the group consisting ofhydrogen, alkali metal, methyl and phenyl), tetrazolyl (wherein thepoint of attachment is the carbon atom of the tetrazole ring and one ofthe nitrogen atoms is mono-substituted by M^(a), as defined previously)and —SO₃ M^(b) (wherein M^(b) is selected from the group consisting ofhydrogen and an alkali metal); d) a hydroxy group: —OH; e) a carbonyloxyradical: —O(C═O)R_(s); wherein R_(s) is a group selected from the groupconsisting of C₁₋₄ alkyl, phenyl and heteroaryl (each of which isoptionally mono- or di-substituted with R^(q), as defined previously);wherein heteroaryl is a monocyclic aromatic hydrocarbon group havingfive or six ring atoms, having at least one carbon atom which is thepoint of attachment; having from one to three carbon atoms replaced by Nin the case of six ring atoms, having one carbon atom replaced by O, Sor N in the case of five ring atoms and, optionally, having up to threeadditional carbon atoms replaced by N; f) a carbamoyloxy radical:—O(C═O)N(R^(y))R^(z); wherein R^(y) and R^(z) are independently selectedfrom the group consisting of H, C₁₋₄alkyl (optionally mono- ordi-substituted by R^(q), as defined previously), a three to fivemembered diradical to form a ring wherein R^(y) and R^(z) are fused(optionally mono- or di-substituted with R^(q), as defined previously)and a two to five membered diradical interrupted by —O—, —S—, —S(O)— or—S(O)₂— to form a ring wherein R^(y) and R^(z) are fused (optionallymono- or di-substituted with R^(q), as defined previously); g) a sulfurradical: —(S═(O)_(n))—R^(s); wherein n is selected from 0, 1 or 2 andR^(s) is as defined previously; h) a sulfamoyl group: —SO₂N(R^(y))R^(z);wherein R^(y) and R^(z) are as defined previously; i) an azido radical:N₃; j) a formylamino group: —(N—R^(t))—(C═O)H; wherein R^(t) is selectedfrom the group consisting of H and C₁₋₄alkyl; wherein the alkyl chain isoptionally mono- or di-substituted by R^(q), as defined previously; k) a(C₁₋₄alkyl)carbonylamino radical: —(N—R^(t))—(C═O)—C₁₋₆alkyl; whereinR^(t) is as defined previously; wherein the alkyl chain is optionallymono-or di-substituted by R^(q), as defined previously; l) a(C₁₋₄alkoxy)carbonylamino radical: —(N—R^(t))—(C═O)—O—C₁₋₄alkyl; whereinR^(t) is as defined previously; wherein the alkyl chain is optionallymono-substituted by R^(q), as defined previously; m) a ureido group:—(N—R_(t))—(C═O)N(R^(y))R^(z); wherein R_(t), R^(y) and R^(z) are asdefined previously; n) a sulfonamido group: —(N—R_(t))SO₂R^(s); whereinR^(s) and R^(t) are as defined previously; o) a cyano group: —CN; p) a(C₁₋₄alkyl)carbonyl radical; wherein the carbonyl is acetalized:—C(OMe)₂C₁₋₄ alkyl; wherein the alkyl is optionally mono-substituted byR^(q), as defined previously; q) a carbonyl radical: —(C═O)R^(s);wherein R^(s) is as defined previously; r) a hydroximinomethyl radical;wherein the oxygen or carbon atom is optionally substituted with aC₁₋₄alkyl group: —CR^(y)═NOR^(z); wherein R^(y) and R^(z) are as definedpreviously; with the proviso that R^(y) and R^(z) may not be joinedtogether to form a ring; s) a (C₁₋₄alkoxy)carbonyl radical:—(C═O)OC₁₋₄alkyl; wherein the alkyl is optionally mono- ordi-substituted by R^(q), as defined previously; t) a carbamoyl radical:—(C═O)N(R^(y))R^(z); wherein R^(y) and R^(z) are as defined previously;u) a N-hydroxycarbamoyl or N(C₁₋₄alkoxy)carbamoyl radical in which thenitrogen atom may additionally be substituted by a C₁₋₄alkyl group:—(C═O)—N(OR_(y))R^(z); wherein R^(y) and R^(z) are as definedpreviously; with that proviso that R^(y) and R^(z) may not be joinedtogether to form a ring; v) a thiocarbamoyl group: —(C═S)N(R^(y))R^(z);wherein R^(y) and R^(z) are as defined previously; w) a carboxylradical: —COOM^(b); wherein M^(b) is as defined previously; x) athiocyanate radical: —SCN; y) a trifluoromethylthio radical: —SCF₃; z) atetrazolyl radical; wherein the point of attachment is the carbon atomof the tetrazole ring and any one nitrogen atom is mono-substituted by asubstituent selected from the group consisting of hydrogen, an alkalimetal and a C₁₋₄alkyl radical; wherein the C₁₋₄alkyl radical isoptionally mono- or di-substituted by R^(q), as defined previously; aa)an anionic function selected from the group consisting of phosphono[P═O(OM^(b))₂], alkylphosphono [p═O(OM^(b))-[O(C₁₋₄alkyl)]],alkylphosphinyl [P═O(OM^(b))-(C₁₋₄ alkyl)], phosphoramido[P═O(OM^(b))N(R^(y))R^(z) and P═O—(OM^(b))NHR^(x)], sulfino (SO₂ M^(b)),sulfo (SO₃ Mb) and acylsulfonamides selected from the group consistingof CONM^(b)SO₂R^(x), CONM^(b)SO₂N(R^(y))R^(z), SO₂NM^(b)CON(R^(y))R^(z)and SO₂NM^(b)CN; wherein R^(x) is selected from the group consisting ofphenyl and heteroaryl; wherein heteroaryl is as defined previously andthe phenyl and heteroaryl substituents are optionally mono- ordi-substituted with R^(q), as defined previously; Mb, R^(y) and R^(z)are as defined previously; ab) a C₅-C₇ cycloalkyl group; wherein any onecarbon atom in the ring is replaced by a heteroatom selected from thegroup consisting of O, S, NH and N(C₁₋₄alkyl); and, in which oneadditional carbon atom may be replaced with NH or N(C₁₋₄alkyl) and inwhich at least one carbon atom adjacent to each nitrogen heteroatom hasboth of its attached hydrogen atoms replaced by one oxygen whereby acarbonyl moiety is formed; with the proviso that there are at most twocarbonyl moieties present in the ring; ac) a C₂-C₄ alkenyl radical;wherein the radical is optionally mono-substituted by a substituentselected from the group consisting of any one of a) to ab) or isoptionally mono-substituted by substituents selected from the groupconsisting of phenyl, pyridyl, quinoline and isoquinoline; wherein eachphenyl, pyridyl, quinoline or isoquinoline substituent is optionallymono- or di-substituted by R^(q), as defined previously; ad) a C₁-C₄alkyl radical; ae) a C₁-C₄ alkyl mono-substituted by a substituentselected from the group consisting of any one of a) to ad); af) a2-oxazolidinonyl moiety; wherein the point of attachment is the nitrogenatom of the oxazolidinone ring; wherein the ring oxygen atom isoptionally replaced by a heteroatom selected from the group consistingof S and NR^(t) (wherein R^(t) is as defined previously) and one of thesaturated carbon atoms of the oxazolidinone ring is optionallymono-substituted by a substituent selected from the group consisting ofany one of a) to ae); ag) a C₂-C₄ alkynyl radical; wherein the radicalis independently selected from the group consisting of any one of a) toaf) and trialkylsilyl; ah) phenyl radicals ai) bicyclic radicals;wherein the radical is independently selected from the group consistingof naphthyl, biphenyl, quinoline, indolizine, indole, isoindole,indoline, benzofuran, indazole, benzimidazole, purine, quinolizine,cinnoline, quinoxaline, phthalazine and quinazoline; aj) heterocyclicradicals; wherein the radical is independently selected from the groupconsisting of furyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl,pyrrolyl, pyrazolyl, imidazolyl, indolyl, thiazolyl, oxazolyl,thiadiazolyl, oxadiazolyl, quinolinyl and isoquinolinyl; and ak) aryland heteroaryl radicals; wherein the radical is independently selectedfrom the group consisting of any one of ah) through aj); wherein theradical is substituted with one to two substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, C₁-C₆alkoxyC₁-C₆alkyl, C₁-C₆alkoxyC₁-C₆alkoxy, C₁-C₆thioalkyl, halogen, cyano, hydroxy, amino, nitro and C₁-C₆alkylamino, inwhich any terminal carbon atom may be replaced by a group selected fromthe group consisting of carboxyl and C₂-C₆alkoxycarbonyl; andpharmaceutically acceptable salts and esters thereof.
 22. Thepharmaceutical composition of claim 21 wherein the condition is acute orchronic pain and the patient is in need of analgesia.
 23. Thepharmaceutical composition of claim 21 wherein the condition or diseaseis Alzheimer's disease, memory loss or dementia or loss of motorfunction.